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Targeting NQO1+ tumor to trigger innate and adaptive immunity

Award Number: R01CA240952
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/13/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Targeting NQO1+ tumor to trigger innate and adaptive immunity - ABSTRACT Our long-term goal is to develop novel antitumor therapies to treat cancer with elevated (> 100-fold) levels of NAD(P)H:quinone oxidoreductase 1 (NQO1). β-Lapachone (β-lap), an NQO1 bioactivatable drug, selectively targets NQO1+ tumors and is activated by NQO1 to generate reactive oxygen species (ROS), leading to extensive DNA damage and PARP1-driven tumor programmed necrosis. Our preliminary studies demonstrate that both neutrophil-mediated innate immunity and CD8-mediated adaptive immunity are required for antitumor efficacy of β-lap in vivo. Furthermore, our previous studies reveal that targeting NQO1 potently triggers innate sensing within tumor microenvironment (TME) that synergizes with immunotherapy to overcome adaptive resistance. Our objective here is to define and delineate the mechanism(s) of tumor-specific ROS and DNA damage induced by β-lap that stimulates antitumor immunity, and determine how β-lap synergizes with immune checkpoint blockade therapy. Our central hypothesis is that (i) β-lap treatment triggers immunogenic cell death (ICD) and induces damage-associated molecular patterns (DAMPs) release;; (ii) phagocytes/antigen-presenting cells (APCs) recruitment promotes cross-priming of cytotoxic T cells (CTLs) for suppression of tumor by increasing antigen/DNA uptake and type I interferons (IFNs) production;; and (iii) upregulated PD-L1 within TME contributes to tumor relapse and provides therapeutic window for combination therapy of β-lap with immune checkpoint blockade. We propose the following Specific Aims. AIM 1: Elucidate the mechanism of β-lap- triggered ICD for innate immune sensing. Our working hypothesis is that β-lap triggers ICD for innate sensing via the release of DAMPs. We will assess the ability of β-lap to stimulate tumor ICD in vivo by therapeutic vaccine assay. We will also determine which type(s) of tumor DNA (genomic or mitochondrial) is the major source(s) of IFNs production after β-lap treatment. AIM 2: Define how tumor cells and immune cells cross-talk occurs in β-lap-induced antitumor immunity. Our working hypothesis is that β-lap-induced neutrophils cross-prime T cells directly or interact with DCs/macrophages to prime T cells. We will determine the effects of β-lap treatment on cGAS/STING/IFNs involved in T cells cross-priming. AIM 3: Determine the mechanism by which β-lap synergizes with immune checkpoint blockade therapy to efficaciously kill NQO1+ tumors. Our working hypothesis is that increased PD-L1 within TME contributes to tumor relapse of large tumors after initial responses to β-lap. We will determine in which type(s) of cells PD-L1 expression is upregulated within TME. We will also determine which type(s) of PD-L1-expressing cells is essential for the synergistic effect in mice with conditional deficiencies of PD-L1 on tumors, DCs or macrophages. IMPACT: These studies will delineate the role of β-lap in tumor-selective innate sensing that leads to T cell-dependent tumor control. Further, we will elucidate how β- lap overcomes adaptive resistance to anti-PD-L1 therapy. This research will provide novel evidence for new combination therapy for NQO1+ solid tumors and broaden the clinical utility of immune checkpoint inhibitors.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2027 ( Subtotal = $0 )
2027	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	5	10/14/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $427,984 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	5	6/20/2024	NON-COMPETING CONTINUATION	$427,984
														Subtotal = $427,984

Issue Date FY: 2023 ( Subtotal = $441,498 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	4	6/6/2023	NON-COMPETING CONTINUATION	$441,498
														Subtotal = $441,498

Issue Date FY: 2022 ( Subtotal = $450,508 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	3	6/28/2022	NON-COMPETING CONTINUATION	$441,498
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	3	8/31/2022	NON-COMPETING CONTINUATION	$9,010
														Subtotal = $450,508

Issue Date FY: 2021 ( Subtotal = $407,082 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	2	6/14/2021	NON-COMPETING CONTINUATION	$407,082
														Subtotal = $407,082

Issue Date FY: 2020 ( Subtotal = $421,360 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	1	7/13/2020	NEW	$421,360
														Subtotal = $421,360

Grand Total All Awards = $2,148,432

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Targeting NQO1+ tumor to trigger innate and adaptive immunity

Award Number: R01CA240952

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/13/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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